Although much effort has been made in sequencing autism exomes, it has been difficult to robustly establish ASD (autism spectrum disorder) candidate genes as bona fide genetic risk factors, as only single mutations are typically observed. Now, Evan Eichler, Jay Shendure and colleagues report ultra-low-cost ASD candidate gene resequencing of 44 genes in 2,446 ASD probands (Science, published online 15 November 2012; doi:10.1126/science.1227764). This resequencing method uses a modified molecular inversion probe (MIP) strategy, such that reagent costs are less than $1 per gene per sample. Applying this method to ASD probands from the Simons Simplex Collection (SSC), the authors identified 27 de novo mutations in 16 genes, with 59% of the mutations predicted to be truncating or disruptive of splicing. Six of the genes (CHD8, GRIN2B, DYRK1A, PTEN, TBR1 and TBL1XR1) have statistically significant evidence of mutation burden; five of these are contained within the β-catenin/chromatin-remodeling network. Altogether, approximately 1% (24/2,573) of ASD probands had a mutation in 1 of these 6 genes. Because the SSC was established for families with simplex ASD and these probands typically possess higher cognitive functioning levels than other ASD cohorts, it is not known how generalizable the mutation burdens of these six genes will be in idiopathic autism.